Paroxysmal Cold Haemoglobinuria

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Paroxysmal Cold Haemoglobinuria

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Paroxysmal cold haemoglobinuria (PCH) is an autoimmune haemolytic anaemia, caused by cold-reacting immunoglobulins. It primarily affects children and tends to cause quite severe, but transient, disease. The usual trigger for the formation of the cold-reacting polyclonal immunoglobulin G (IgG) autoantibodies is an episode of infection. The episode usually, but not always, follows a period of exposure to cold. It is usually a transient postinfectious or postvaccination problem that resolves, but it may cause significant morbidity. The degree of haemolysis is variable but may lead to an acute onset of intravascular haemolysis and haemoglobinuria.

Cross-reactivity (between antibodies formed against microbial antigens and the red-cell membrane P-antigen) induces intravascular haemolysis through complement activation. The antibodies detectable in the blood of those who suffer from PCH are known as 'Donath-Landsteiner antibodies'.[1]

Epidemiology

It is a very rare illness; there are no reliable population-incidence figures, but it is believed to be responsible for about 40% of all autoimmune haemolytic anaemias that affect children (lower percentage for adults).[2] Autoimmune haemolytic anaemias are, however, very rare, with an annual incidence of <1 per 100,000 population.[3]

Although the vast majority of cases occur in children, adults may rarely be affected.[4] The acute, transient form of paroxysmal cold haemoglobinuria (by far the most usual modern presentation) is much more common in children than in adults.

Signs

Pallor and tachycardia are likely to be present and the abdomen should be examined for evidence of hepatosplenomegaly (possible underlying neoplasm).

Lymph node areas should be examined and the chest checked for evidence of current infection.

The condition used to be strongly associated with congenital syphilis before its decline in developed countries; there may be signs of congenital syphilis, particularly for children in/from countries with a high incidence of syphilis.[2]

Investigations

Investigations include assessment of the haemolytic anaemia and identification of any underlying cause.

Urinalysis: haemoglobinuria will be present to varying degrees at presentation; examine the urine for colour and dipstick for haemoglobin, proteinuria may also occur.

Full blood count: may show acute anaemic picture, ranging from mild to severe. Usually normochromic, normocytic pattern. May appear as macrocytic anaemia during acute haemolytic phase. Paradoxically for a haemolytic anaemia, there is often a low reticulocyte count in the early stages. Subsequently reticulocytosis tends to occur as the marrow pushes out cells to replace those that have been lost. White cell count can be low in early stages but tends to be normal or high if infection is a factor.

Autoantibody detection: a specialist indirect IgG antiglobulin test performed at low temperature may detect anti-P Donath-Landsteiner antibodies. The Donath-Landsteiner bithermic haemolytic test is not very sensitive but quite specific, especially if utilising the cells of a patient with paroxysmal nocturnal haemoglobinuria. The patient's red blood cells are incubated with serum and complement at a low temperature and then at body temperature; the presence of haemolysis indicates a positive test.

Blood typing: group and save in case of need for transfusion. Cross-matching can be difficult as autoantibody may agglutinate donor cells that would not normally be reactive. Specialist transfusion medicine input may be required.

Direct Coombs' test: is negative.

Management

Children suspected of suffering from the condition should be referred urgently to their local acute paediatric service.

Keep the patient warm with extremities covered during the acute phase of the illness.

Cross-matching requires special attention due to the interfering effect of the autoantibody. Most banked blood donations are P-antigen positive but can be used safely in most cases, after rigorous specialist testing.

Transfusions should be given washed, warmed and in packed-cell format. If active bacterial infection is suspected then treat with appropriate intravenous antibiotics.

Close attention must be paid to fluid status and consideration given to alkalinisation of urine.

Steroids are occasionally used but there is no good evidence for their effectiveness.

After the acute phase is over, patients should be followed up for a few months in the haematology clinic. They may require daily/weekly review at first. Regular blood counts and other tests will be used to check the problem is resolving.

The syndrome may recur and patients should be advised to avoid cold exposure during this time.

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